I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US008664231B2
`
`c12) United States Patent
`Will
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,664,231 B2
`Mar. 4, 2014
`
`(54) CONCENTRATED METHOTREXATE
`SOLUTIONS
`
`(75)
`
`Inventor: Heiner Will, Hamburg (DE)
`
`(73) Assignee: Medac Gesellschaft fuer Klinische
`Spezialpraepararate mbH, Wedel (DE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 682 days.
`
`(21) Appl. No.:
`
`12/374,528
`
`(22) PCT Filed:
`
`Jul. 20, 2007
`
`(86) PCT No.:
`
`PCT /EP2007 /006491
`
`§ 371 (c)(l),
`(2), ( 4) Date: Mar. 4, 2009
`
`(87) PCT Pub. No.: W02008/009476
`
`PCT Pub. Date: Jan. 24, 2008
`
`(65)
`
`Prior Publication Data
`
`US 2010/0016326Al
`
`Jan.21,2010
`
`(30)
`
`Foreign Application Priority Data
`
`Jul. 21, 2006
`
`(DE) ......................... 10 2006 033 837
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`AOlN 43/90
`A61K 31/519
`(52) U.S. Cl.
`....................................................... 514/262.1
`USPC
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,542,934 A *
`
`8/1996 Silver ............................ 604/191
`
`OTHER PUBLICATIONS
`
`Hoekstra et al. (J Rheumatol, vol. 31, pp. 645-648; 2004).*
`Wright et al. (International Journal of Pharmaceutics, vol. 45, Issue 3,
`abstract; 1988).*
`Galinsky et al. ["Basic Pharmacokinetics and Pharmacodynamics."
`in: Remington: The Science and Practice of Pharmacy (Baltimore,
`Lippincott Williams & Wilkins, 2006), p. 1171]. *
`Jansen MM PM et al., "Methotrexate Outside the Clinic, Intramus(cid:173)
`cular and Subcutaneous Administration to Patients with Rheumatoid
`
`Arthritis" Pharmaceutisch Weekblad (1999) pp. 1592-1596, vol.
`134(46), as recited in the Int'! Search Report, filed Jul. 20, 2007.
`Rote Liste Service, GMBH, Rote Liste 1999ECV, Editio Cantor
`Verlag, Aulendorf (1999) XP002491051, Abstract No. 86042, as
`recited in Int'! Search Report filed Jul. 20, 2007.
`Kurnik, D. et al., "Bioavailability of Oral vs. Subcutaneous Low(cid:173)
`Dose Methotrexate in Patients with Crohn's Disease" Alimentary
`Pharmacology & Therapeutics (2003), pp. 57-63, vol. 18(1).
`Hoekstra, M. et al., "Bioavailability oh Higher Dose Methotrexate
`Comparing Oral and Subcutaneous Administration in Patients with
`Rheumatoid Arthritis" Journal ofRheumatology(2004) pp. 645-648,
`vol. 31(4).
`Zackheim, H. et al., "Subcutaneous Administration ofMethotrexate"
`Journal of the American Academy of Dermatology ( 1992) pp. 1008,
`vol. 26(6).
`European Search Report dated May 4, 2011 issued in corresponding
`EP Patent Application No. 10 19 4145.8.
`Pharmachemie BV, Physician Package Insert, Abitrexate (Feb. 22,
`2000).
`Methotrexate 100 mg/ml Injection Package Insert, Hospira UK Ltd.
`(Jun. 7, 1994).
`Injection in Prefilled,
`Wright, M. P. et al., "Stability ofMethotrexate
`Plastic Disposable Syringes" International Journal of Pharmaceutics
`(1988) pp. 237-244, vol. 45.
`O'Dell, J.R., "Methotrexate Use in Rheumatoid Arthritis" Rheumatic
`Disease Clinics of North America Nov. 1997) pp. 779-796, vol. 23,
`No.4.
`Brooks, P. J. et al., "Pharmacokinetics ofMethotrexateAdministered
`by Intramuscular and Subcutaneous Injections in Patients with Rheu(cid:173)
`matoid Arthritis" Arthritis and Rheumatism (Jan. 1990) pp. 91-94,
`vol. 33, No. 1.
`Silverman, E. et al., "Leflunomide or Methotrexate for Juvenile
`Rheumatoid Arthritis" The New England Journal of Medicine (Apr.
`21, 2005) pp. 1655-1666, vol. 352.
`Balis, F. M. et al., "Pharmacokinetics of Subcutaneous Methotrex(cid:173)
`ate" Journal of Clinical Oncology(Dec.1988)pp.
`1882-1886, vol. 6,
`No.12.
`European Opposition Brief dated Sep. 15, 2011 received in corre(cid:173)
`sponding Ep Patent Application No. 2 046 332.
`English translation of the decision issued by the Opposition Division
`on Nov. 19, 2012 in European Patent No. EP-B-2 046 332.
`* cited by examiner
`
`Jeffrey S. Lundgren
`Primary Examiner -
`Assistant Examiner - Michael Schmitt
`(74) Attorney, Agent, or Firm - Scully, Scott, Murphy &
`Presser, P.C.
`
`ABSTRACT
`(57)
`Concentrated methotrexate solutions are described which are
`suitable for the use of an active substance in the production of
`a parenterally administered medicament for the treatment of
`inflammatory autoimmune diseases. The methotrexate
`is
`added to a pharmaceutically acceptable solvent at a concen(cid:173)
`tration of more than 30 mg/ml. The invention also relates to a
`ready-made syringe and a carpule containing such a pharma(cid:173)
`ceutical solution formulation, as well as a pen injector com(cid:173)
`prising such a carpule and/or a ready-made syringe.
`
`22 Claims, No Drawings
`
`Page 1 of 6
`
`KOIOS Exhibit 1001
`
`

`
`US 8,664,231 B2
`
`1
`CONCENTRATED METHOTREXATE
`SOLUTIONS
`
`The present invention relates to concentrated methotrexate
`solutions. In particular, the present invention relates to the use
`of methotrexate in the production of a parenterally adminis(cid:173)
`tered medicament for the treatment of inflarmnatory autoim(cid:173)
`mune diseases, wherein the methotrexate is present in a phar(cid:173)
`maceutically acceptable solvent at a concentration of more
`than 25 mg/ml. The invention also relates to a ready-made
`syringe and a carpule containing such a pharmaceutical solu(cid:173)
`tion formulation, as well as a pen injector comprising such a
`carpule and/or a ready-made syringe.
`The pharmaceutical active substance N-{ 4-[ (2,4-diamino-
`6-pteridinylmethyl)methylamino ]-benzoyl }-L-glutamic acid
`(INN: methotrexate, in short: MTX) has been known since the
`early 1950s. Methotrexate is a folic acid antagonist. As an
`antimetabolite of nucleic acid synthesis, it causes an intrac(cid:173)
`ellular inhibitation of debydrofolate reductase (irreversible
`bond) with a consecutive inhibition of purine synthesis,
`inhibits LTB4 synthesis in neutrophils, inhibits IL-1 synthe(cid:173)
`sis, suppresses cell-mediated immunity and inhibits endothe(cid:173)
`lial cell proliferation.
`Due to its effectiveness as a cytostatic agent, methotrexate
`has long been used predominantly in the field of oncology. In
`particular, it was used to treat breast cancer, but also for the
`treatment ofleukemia in children. To this day, methotrexate is
`still highly significant for the latter indication. The effective(cid:173)
`ness of methotrexate in the treatment of psoriasis was discov(cid:173)
`ered early on. Since psoriasis can accompany rheumatoid
`arthritis, this therapy option was first observed in the late
`1950s in individual cases as well.
`Rheumatoid arthritis is usually therapeutically treated with
`fast-acting pain-relieving and short-term anti-inflarmnatory
`substances. In this connection, non-steroidal antirheumatics
`(NSAR, e.g. the active substance diclofenac) and corticoids
`can be mentioned. However, these substances do not influ(cid:173)
`ence the actual course of the disease. In most patients, NSAR
`and corticoids are only used until the pain and inflarmnation
`subside considerably. Then the dosage is often reduced or the 40
`drug is tapered completely.
`Only disease-modifying anti-rheumatic drugs (DMARDs)
`have a disease-modifying effect in rheumatoid arthritis. In
`addition to methotrexate, examples of these substances,
`which are also referred to as basic therapeutics, include aza- 45
`thioprine, sulfasalazine and anti-malaria substances. Basic
`therapeutics directly intervene in the course of the disease and
`can decelerate the progression of the disease, which is why
`they should be administered as early as possible. Since rheu(cid:173)
`matoid arthritis is a chronic disease, the basic therapeutics 50
`usually have to be taken for long periods of time; if the drugs
`are effective and well tolerated, the treatment is often contin(cid:173)
`ued throughout the patients lifetime (continuous long-term
`therapy) whereby the dosage of the active substance can be
`adapted to the course of the disease.
`Contrary to chemotherapy in the treatment of tumors,
`methotrexate as a basic therapeutic in the treatment of rheu(cid:173)
`matoid arthritis is dosed significantly lower, sometimes up to
`1000 times lower, which is why the antirheumatic therapy is
`also referred to as "low-dosage methotrexate therapy". In 60
`Germany, a dosage range of 5.0 to 30.0 mg per week is
`common for antirheumatic therapy, in other European coun(cid:173)
`tries, dosages ofup to 40.0 mg per week are administered. It
`is extremely important that methotrexate only be adminis(cid:173)
`tered once a week.
`In principle, methotrexate can be administered orally and
`parenterally. However, after a long time of oral therapy based
`
`2
`on tablets, parenteral formulations are now being used since it
`has been found that methotrexate is resorbed more reliably
`from tablets and thus no sufficient accuracy can be guaranteed
`in dosage-dependent
`therapy. Cytostatics
`suitable
`for
`parenteral administration are usually prepared by dissolving
`the active substance in a suitable solvent, using a specific
`amount of active substance for each individual patient. How(cid:173)
`ever, handling cytostatics and preparing cytostatics-contain(cid:173)
`ing medicaments is not without challenges and subject to
`10 strict legal restrictions. For example, cytostatics cannot be
`prepared outside of a suitable venting system provided espe(cid:173)
`cially for this purpose. Since rheumatologists and general
`practitioners usually do not have such systems at their dis(cid:173)
`posal, they are not authorized to prepare methotrexate them-
`15 selves, whereby even drawing up a syringe from a bottle (for
`example an injection bottle containing the active substance
`solution) is considered a preparation.
`For this reason, ready-made syringes were developed in
`order to eliminate this step of drawing up a syringe. For the
`20 first time, the applicant in the present invention was able to
`have such ready-made syringes for subcutaneous application
`approved throughout Europe. These ready-made syringes
`allow the use by the physician, the medical staff, or, in case of
`self-application, by the patient himself without a pharmacist
`25 having a suitable vent system at his disposal as a go-between.
`Ready-made syringes for parenteral administration con(cid:173)
`taining methotrexate solutions wherein the active substance is
`present at a concentration ofup to 25 mg/ml in a pharmaceu(cid:173)
`tically acceptable solvent (trade names: Lantarel® of the
`30 company Wyeth, Metex® of the applicant) are known from
`the prior art for the treatment of rheumatoid arthritis, wherein
`the injection solution Lantarel® with the concentration 25
`mg/ml (trade name: Lantarel® FS 25 mg) is not approved for
`subcutaneous application. Over the years, methotrexate has
`35 become the gold standard in the treatment of rheumatoid
`arthritis.
`As has already been described above, a successful basic
`therapy with methotrexate requires that the rheumatic patient
`be administered a suitable dose of methotrexate once a week
`over a very long period of time, sometimes throughout his
`entire lifetime. Due to its more advantageous bioavailability,
`parenteral application is superior to oral application Further-
`more, children in particular exhibit a certain aversion to tak(cid:173)
`ing tablets. However, it has been found that a subcutaneous
`administration in particular has its difficulties. When treated
`with the preparations known from the prior art, patients
`showed a disapproving attitude. This was due to the problem
`of having to inject the required relatively large amount of
`active substance solution (e.g. up to 3 ml in the case of a
`certain dosage) under the skin every week, which was espe(cid:173)
`cially difficult to convey to children, including the weekly
`doctor's visit.
`There is therefore a need for pharmaceutical formulations
`of methotrexate which can be administered to the patient,
`55 including children, as easily and pain-free as possible, while
`providing good bioavailability, over a long period of time at
`regular intervals, in particular weekly, which therefore leads
`to a high degree of patient compliance. As an added advan-
`tage, the patient should be able to self-administer the phar(cid:173)
`maceutical formulation.
`The object underlying the present invention is therefore to
`provide a pharmaceutical formulation for the treatment of
`inflammatory autoimmune diseases, in particular rheumatoid
`arthritis, which overcomes the disadvantages of the prior art
`65 preparations described above.
`The object underlying the present invention is achieved by
`the subject matter of the patent claims.
`
`Page 2 of 6
`
`KOIOS Exhibit 1001
`
`

`
`US 8,664,231 B2
`
`20
`
`3
`In a first embodiment, the invention relates to the use of
`methotrexate in the production of a parenterally administered
`medicament for the treatment of inflammatory autoimmune
`diseases, wherein the methotrexate is present in a pharmaceu(cid:173)
`tically acceptable solvent at a concentration of more than 25
`mg/ml.
`In another embodiment, the invention relates to a ready(cid:173)
`made syringe containing such a pharmaceutical solution for(cid:173)
`mulation of methotrexate in a pharmaceutically acceptable
`solvent at a concentration of more than 25 mg/ml.
`Furthermore, in another embodiment, the invention relates
`to a carpule containing a pharmaceutical solution formulation
`of methotrexate in a pharmaceutically acceptable solvent at a
`concentration of more than 25 mg/ml, as well as a pen injector
`comprising such a carpule.
`According to the present invention, medicaments or phar(cid:173)
`maceutical solution formulations are provided which com(cid:173)
`prise methotrexate at a concentration of more than 25 mg/ml
`in a pharmaceutically acceptable solvent. In a preferred
`embodiment, the methotrexate is present in the medicament
`at a concentration of more than 25 mg/ml to about 150 mg/ml.
`Furthermore, concentration
`ranges of 30 mg/ml to 100
`mg/ml, and in particular 40 mg/ml to 80 mg/ml and further(cid:173)
`more 50 mg/ml to 75 mg/ml, are preferred In an especially
`preferred embodiment,
`the methotrexate
`is present in the 25
`medicament at a concentration of about 50 mg/ml in a phar(cid:173)
`maceutically acceptable solvent.
`All solvents which are pharmaceutically acceptable and
`are not incompatible with the active substance or other pos(cid:173)
`sible components of the medicament or the pharmaceutical
`solution formulation can be used as the pharmaceutically
`acceptable solvent. According to the present invention, espe(cid:173)
`cially suitable solvents include water, in particular water for
`injection purposes, water comprising isotonization additives
`and sodium chloride solution, in particular isotonic sodium 35
`chloride solution. Water for injection purposes is especially
`preferred. Examples of
`isotonization additives
`include
`soluble salts (sodium chloride, potassium chloride), sugars
`(glucose, lactose), sugar alcohols (mannitol, sorbitol) as well
`as combinations of these additives.
`In addition to isotonization additives, the medicament
`according to the present invention can comprise additives
`common in the field of pharmaceutical solution formulations.
`In particular, the medicament according to the present inven(cid:173)
`tion can comprise additives with the following functionality:
`Eu-/isohydration (acetate, phosphate, citrate buffers), anti(cid:173)
`oxidants ( ascorbic acid, sulfur compounds common in the
`technical field), solubility promoters ( complexing agents,
`solubilizers, co-solvents: e.g. cyclodextrine, polyvidone,
`lecithin, glycocholate ), increasing viscosity,
`polysorbate,
`adjusting pH (acids, bases, or acidic or basic salts). In an
`especially preferred embodiment, the pH value of the medi(cid:173)
`cament according to the present invention is between 7.5 and
`9.
`
`The medicaments according to the present invention are 55
`directed to the treatment of inflammatory autoimmune dis(cid:173)
`eases. The term "inflammatory autoimmune disease" encom(cid:173)
`passes all inflammatory autoimmune diseases which can rea(cid:173)
`sonably be
`treated with methotrexate. Examples of
`inflammatory autoimmune diseases which can be treated with
`the medicament according to the present invention include,
`but are not limited to, rheumatoid arthritis, juvenile arthriti(cid:173)
`des, vasculitides, collagenoses, Crohn's disease, colitis ulce(cid:173)
`rosa, bronchial asthma, Alzheimer's disease, multiple sclero(cid:173)
`sis, Bechterew's disease, joint arthroses or psoriasis, as well
`as psoriasis arthritis and in particular plaque-type psoriasis
`vulgaris. The medicaments of the present invention are espe-
`
`4
`cially preferred for the treatment of rheumatoid arthritis,
`includingjuvenile arthritides, such as specifically the oligoar(cid:173)
`thritic and polyarthritic forms of juvenile arthritis.
`The medicaments of the present invention are administered
`parenterally. In particular, the medicaments are administered
`by intravenous,
`intramuscular or subcutaneous
`injection.
`According to a preferred embodiment of the present inven(cid:173)
`tion, the medicament
`is present in such a form which is
`It is furthermore
`suitable for subcutaneous administration.
`10 preferred that the medicament be present in a form which
`allows subcutaneous self-administration by the patient (self(cid:173)
`application). Such a treatment of subcutaneous self-adminis(cid:173)
`tration has for example proven successful in the administra(cid:173)
`tion of insulin by the diabetic himself and leads to a high
`15 degree of treatment acceptance on the part of the patient
`(patient compliance). In the case ofrheumatism,
`self-appli(cid:173)
`cation also has the advantage that the weekly doctor's visit is
`no longer necessary.
`In a preferred embodiment of the present invention, the
`medicament according to the present invention is contained in
`an injection device for a single application, in particular a
`ready-made syringe. According to the present invention, an
`injection device for a single application is a device which in
`addition to a vessel containing the pharmaceutical solution
`formulation according to the present invention comprises an
`injection needle (hypodermic needle) through which the
`medicament can be administered to the patient. Furthermore,
`such an injection device comprises a mechanical part (e.g. a
`stamp or a flexible bubble), by means of which the medica(cid:173)
`ment can be pushed from the container through the injection
`needle. Such an injection device for a single application is
`furthermore characterized in that it contains a specific single
`dose of the active substance and thus that during application
`the vessel containing the pharmaceutical solution formula(cid:173)
`tion according to the present invention has to be emptied
`completely in order to administer the prescribed dosage. Due
`to this fact, it is usually unnecessary in this embodiment to
`add a preservative to the pharmaceutical solution formulation
`of methotrexate.
`An injection device for a single application according to
`the present invention preferably contains a dose of the active
`substance methotrexate of 5 mg to 40 mg. It is especially
`preferred that an injection device for a single application
`according to the present invention contain a dose of 5.0, 7.5,
`45 10.0, 12.5, 15.0, 17.5, 20.0, 22.5, 25.0, 27.5, 30.0, 32.5, 35.0,
`37.5 or 40.0 mg. The volume of the liquid necessary to pro(cid:173)
`vide the desired dose, which has to be contained in the injec(cid:173)
`tion device for a single application, depends on the concen(cid:173)
`tration of the active substance solution and is obvious to the
`50 person skilled in the art. Thus, in order to provide a dose of
`active substance of30.0 mg at a methotrexate concentration
`in the pharmaceutically acceptable solvent of for example 50
`mg/ml, an injection device for a single application would
`have to contain a liquid volume of0.6 ml.
`An especially preferred example of an injection device for
`a single application according to the present invention is a
`ready-made syringe. Ready-made syringes are well-known in
`the pharmaceutical field, in particular also in the treatment of
`rheumatoid
`arthritis with methotrexate. Ready-made
`60 syringes containing methotrexate solutions with concentra(cid:173)
`tions of 7.5 mg/ml, 10.0 mg/ml and 25 mg/ml are already
`being distributed on the German market (trade names: Lan(cid:173)
`tarel® of the company Wyeth, Metex® of the applicant,
`whereby the commercial product Lantarel® FS 25 mg is not
`65 approved for subcutaneous application). Although the provi(cid:173)
`sion of methotrexate solutions in ready-made syringes, some
`for self-application, have had a positive impact on patient
`
`30
`
`40
`
`Page 3 of 6
`
`KOIOS Exhibit 1001
`
`

`
`US 8,664,231 B2
`
`5
`compliance, the prior art preparations that are approved for
`subcutaneous application have the disadvantage that, depend(cid:173)
`ing on the amount of active substance to be administered in
`each week, relatively large amounts of liquid have to be
`injected under the patient's skin. In the case of a common
`weekly dosage of active substance of 30 mg, this means that
`based on the currently highest concentration of active sub(cid:173)
`stance solution for subcutaneous application of the prior art,
`namely 10 mg/ml (in the commercial product Metex® 10
`mg/ml of the applicant), a volume of3 ml has to be injected
`under the skin. This large amount of liquid is often hard to
`convey to the patient, in particular children, which leads to a
`reduced patient compliance.
`The medicaments provided by the present invention on the
`other hand contain highly concentrated solutions of the active
`substance methotrexate which results in a reduction of the
`amount of liquid to be administered with a certain weekly
`active substance dosage. For example, in the case of an espe(cid:173)
`cially preferred concentration of 50 mg/ml according to the
`present invention, it would be sufficient to administer a liquid
`volume of only 0.6 ml subcutaneously in order to keep with a
`weekly active substance dosage of30 mg. It can be expected
`that this has a positive impact on patient compliance.
`Thus, in a preferred embodiment, the present invention
`provides a ready-made syringe containing a pharmaceutical
`solution formulation of methotrexate at a concentration of
`more than 25 mg/ml in a pharmaceutically acceptable sol(cid:173)
`vent. Ready-made syringes are well known in the pharma(cid:173)
`ceutical field and are not restricted in any way in the present
`invention. Ready-made syringes according to the present
`invention for example also encompass disposable injection
`systems such as the Uniject®
`injection system. In one
`embodiment, the ready-made syringe can already be provided
`with a suitable hypodermic needle for intravenous, intramus(cid:173)
`cular or subcutaneous injection; in an alternative embodi(cid:173)
`ment, the ready-made syringe is at first provided with a rubber
`tip or the like which prior to application is replaced with a
`separately packaged sterile hypodermic needle by the physi(cid:173)
`cian, the medical staff, or, in case of self-application, by the
`patient himself.
`to the
`Preferably,
`the ready-made syringe according
`present invention is designed such that it is suitable for the
`subcutaneous application of the active substance solution,
`which can be achieved by providing a hypodermic needle
`suitable for subcutaneous injection. In a preferred embodi(cid:173)
`ment, the ready-made syringe is constructed such that even
`rheumatic patients with limited fine motor skills who may not
`necessarily be able to self-inject a medicament with conven(cid:173)
`tional ready-made syringes, can carry out a self-administra(cid:173)
`tion. In particular, the stamp and back stop are constructed 50
`and sized such that handling is facilitated for the rheumatic
`patient. Ready-made syringes with that type of design are
`known in the prior art.
`In another preferred embodiment of the present invention,
`the medicament according to the present invention is con- 55
`tained in a storage container. A storage container according to
`the present invention can be any container commonly used in
`the technical field in which the medicament or the pharma(cid:173)
`ceutical solution formulation according to the present inven(cid:173)
`tion can be filled and stored professionally, i.e. in particular in 60
`a sterile manner. Examples of storage containers include, but
`are not limited to, an injection bottle, a vial, a bag, a glass
`ampoule, or a carpule. According to an embodiment of the
`present invention, in order to administer the medicament to
`the patient, the desired amount of pharmaceutical solution 65
`formulation first has to be drawn up from the storage con(cid:173)
`tainer (for example an injection bottle) by means of an injec-
`
`6
`tion device (for example a conventional disposable syringe),
`while according to an alternative embodiment of the present
`invention the pharmaceutical solution formulation can be
`administered directly from the storage container (for example
`a carpule) by means of an injection device (for example a pen
`injector).
`In a preferred embodiment of the invention the storage
`container comprises, in addition to the active substance meth(cid:173)
`otrexate dissolved in the pharmaceutically acceptable sol-
`lO vent, at least one preservative. The preservative suitable for
`use in the present invention is not particularly restricted and a
`person skilled in the art will have no difficulties selecting a
`suitable preservative from the preservatives commonly used
`15 for pharmaceutical purposes. Preferred preservatives include
`cresols, benzyl alcohols, and phenyl ethyl alcohols. The main
`purpose of the preservative is to preserve the pharmaceutical
`solution formulation remaining
`in the storage container
`according to the present invention (for example an injection
`20 bottle or a carpule) after a portion of the medicament has been
`removed (for example by means of a conventional disposable
`syringe or a pen injector).
`The total dosage amount of the active substance methotr(cid:173)
`exate in a storage container according to the present invention
`25 is not particularly restricted and in addition to the used con(cid:173)
`centration of methotrexate in the pharmaceutically accept(cid:173)
`able solvent is largely determined by the dimensions of the
`storage container and thus the amount of liquid the storage
`container can accommodate. Preferably, the storage container
`30 of the present invention contains a total dosage amount of 5 to
`5,000 mg methotrexate.
`A preferred example of a storage container containing the
`medicament according to the present invention is a carpule.
`35 Carpules, also referred to as syringe cartridges, are well
`known in the art. To the person skilled in the art, a carpule is
`a preferably cylindrical sterile drug receptacle preferably
`made from glass or a preferably transparent inert plastic ( e.g.
`Topas®). On one side of carpule cylinder there is usually a
`40 movable end plug, and on the other side a pierceable mem(cid:173)
`brane made from rubber or a comparable elastic sealing mate(cid:173)
`rial. For the application of the medicament, the pharmaceu(cid:173)
`tical preparation in the carpule is pressed out of the carpule
`through a hypodermic needle which pierces the rubber mem-
`45 brane described above by exerting pressure on the movable
`end plug with e.g. an external stamp or piston.
`In another embodiment, the present invention therefore
`provides a carpule containing a pharmaceutical solution for(cid:173)
`mulation of methotrexate at a concentration of more than 25
`mg/ml in a pharmaceutically acceptable solvent. In a pre(cid:173)
`ferred embodiment, the carpule according to the present
`invention contains a total dosage amount of 5 to 500 mg,
`especially preferred 7 .5 to 300 mg, of methotrexate.
`The medicament is preferably administered from the car-
`pule by means of an injection device. In an especially pre(cid:173)
`ferred embodiment of the present invention, the carpule is
`therefore suitable for the application of the medicament via
`an injection device. Such injection devices are well known in
`the art. Preferably, one such injection device is a so-called pen
`injector, into which the carpule can be inserted. Pen injectors
`usually look like large fountain pens and are in particular
`commonly used by diabetics for comfortably injecting the
`insulin dose they require. After the inserted carpule has been
`emptied, a new carpule can easily be inserted in the pen
`injector ( comparable to the replacement of an ink cartridge in
`the fountain pen mentioned above as a comparison).
`
`Page 4 of 6
`
`KOIOS Exhibit 1001
`
`

`
`US 8,664,231 B2
`
`8
`solution is obtained whose pH is stable between 8.5 and 8.9.
`The final volume was obtained by adding the remaining
`amount of water for injection purposes.
`By means of sterile filtration through a 0.22 µm sterile filter
`the solution was filled into the provided sterile glass recep(cid:173)
`tacles of glass type 1 ( carpules or ready-made syringes) using
`protective gas (nitrogen) under clean-room conditions (class
`A).
`
`Example 2
`
`The methotrexate solution described below (concentra(cid:173)
`tion: 50 mg/ml) was prepared from the following compo(cid:173)
`nents.
`
`Methotrexate disodium:
`Sodium chloride:
`Water for injection purposes:
`Total:
`
`1,645 g
`120 g
`ad 30,684 g
`30,684 g - 30 liters
`
`7
`Thus, in another embodiment, the present invention pro(cid:173)
`vides a pen injector comprising the above-described carpule
`of the present invention containing the medicament of the
`present invention.
`A pen injector according to the present invention is pref(cid:173)
`erably designed such that it is suitable for the subcutaneous
`application of the active substance which can in particular be
`achieved by the provision of a hypodermic needle suitable for
`subcutaneous injection. Furthermore, a pen injector accord(cid:173)
`ing to the present invention and the carpule contained therein 10
`are preferably designed such that multiple applications of
`single dosages can be carried out. For this purpose, a pen
`injector according to the present invention preferably com(cid:173)
`prises a structural device ( e.g. a control dial) by means of
`which a certain dosage of the methotrexate to be administered 15
`can be adjusted (i.e. specifically the selection of a certain
`application volume in combination with a known active sub(cid:173)
`stance concentration of methotrexate in the pharmaceutical
`solution formulation) by the physician, the medical staff, or,
`in case of self-application, by the patient himself. Thus, with 20
`this embodiment, the present invention also offers the possi(cid:173)
`bility of selecting, if desired, intermediate dosages for which
`no other storage containers or injection devices, in particular
`no other injection bottles or ready-made syringes, are com(cid:173)
`mercially available. Pen injectors with that type of structure 25
`are well known in the art, especially from the field of insulin
`injectors.
`According to a preferred embodiment of the invention, a
`pen injector according to the present invention is designed
`such that the single dosages per application can be adjusted 30
`from 5 to 40 mg methotrexate. In particular, a pen injector
`according to the present invention can be adjusted such that
`per application a single dosage of 5.0, 7.5, 10.0, 12.5, 15.0,
`17.5, 20.0, 22.5, 25.0, 27.5, 30.0, 32.5, 35.0, 37.5 or 40.0 mg
`can be administered.
`The invention is described in more detail in the following
`examples which are not intended to restrict the invention in
`anyway:
`
`35
`
`For preparing the solution (Example 2), about 60% of the
`required water for injection purposes (20-25° C.) was pro(cid:173)
`vided in the solution vessel. The agitator was switched on and
`the amount of sodium chloride listed above was added and
`dissolved completely. The vessel and the solution were
`flooded with nitrogen, which essentially displaced
`the
`residual dissolved oxygen. The amount of methotrexate listed
`above was dissolved in the solution while the agitator was
`running. The temperature of the solution is between 20 and
`30° C. The solution is clear and the pH value is stable between
`8.5 and 8.9. The final volume was obtained by adding the
`remaining amount of water for injection purposes.
`By means of sterile filtration through a 0.22 µm sterile filter
`the solution was filled into the provi